WO1999047125A1 - Comprimes oraux a noyau monolithique a liberation controlee - Google Patents
Comprimes oraux a noyau monolithique a liberation controlee Download PDFInfo
- Publication number
- WO1999047125A1 WO1999047125A1 PCT/US1999/006024 US9906024W WO9947125A1 WO 1999047125 A1 WO1999047125 A1 WO 1999047125A1 US 9906024 W US9906024 W US 9906024W WO 9947125 A1 WO9947125 A1 WO 9947125A1
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- WO
- WIPO (PCT)
- Prior art keywords
- controlled release
- release pharmaceutical
- pharmaceutical tablet
- drug
- hours
- Prior art date
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- 150000005691 triesters Chemical class 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0004—Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/282—Organic compounds, e.g. fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
Definitions
- the present invention relates to controlled release unit dose formulations containing an antihyperglycemic drug. More specifically, the present invention relates to an oral dosage form comprising a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride or the metformin salts described in United States Patent Nos . 3,957,853 and 4,080,472 which are incorporated herein by reference.
- a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof
- metformin hydrochloride or the metformin salts described in United States Patent Nos . 3,957,853 and 4,080,472 which are incorporated herein by reference.
- antihyperglycemic drug wherein the bioavailability of the drug is not decreased by the presence of food.
- an antihyperglycemic drug (i) an antihyperglycemic drug; (ii) optionally a binding agent; and (iii) optionally an absorption enhancer;
- the dosage form of the present invention can provide therapeutic levels of the antihyperglycemic drug for twelve to twenty- four hour periods and does not exhibit a decrease in bioavailability if taken with food. In fact, a slight -.
- the controlled release dosage form of the present invention is administered with food.
- the dosage form will be administered once a day, ideally with or after a meal and most preferably with or after the evening meal, and provide therapeutic levels of the drug throughout the day with peak plasma levels being obtained between 8-12 hours after administration .
- FIG. 1 is a graph which depicts the dissolution profile in simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid (SGF) of the formulation described in Example 1 as tested according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
- simulated intestinal fluid pH 7.5 phosphate buffer
- SGF simulated gastric fluid
- FIG. 2 is a graph which depicts the dissolution profile in simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid (SGF) of the formulation described in Example 2 as tested according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
- simulated intestinal fluid pH 7.5 phosphate buffer
- SGF simulated gastric fluid
- FIG. 3 is a graph which depicts the dissolution profile in simulated intestinal fluid (pH 7.5 phosphate buffer) and simulated gastric fluid (SGF) of the formulation described in Example 3 as tested according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm.
- FIG. 4 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 1 and the in vivo metformin plasma profile of the commercially available metformin HCl product GLUCOPHAGE ® under fasting conditions.
- FIG. 5 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 2 and the in vivo metformin plasma profile of the commercially available metformin HC1 product GLUCOPHAGE ® under fasting conditions.
- FIG. 6 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 2 and the in vivo metformin plasma profile of the commercially available metformin HCl product GLUCOPHAGE ® under fed conditions.
- FIG. 7 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 3 and the in vivo metformin plasma profile of the commercially available metformin HCl product GLUCOPHAGE ® under fed conditions (after breakfast) .
- FIG. 8 is a graph depicting the in vivo metformin plasma profile of the formulation described in Example 3 and the in vivo metformin plasma profile of the commercially available metformin HCl product GLUCOPHAGE ® under fed conditions (after dinner) .
- antihyperglycemic drugs refers to drugs that are useful in controlling or managing noninsulin-dependent diabetes mellitus (NIDDM) .
- NIDDM noninsulin-dependent diabetes mellitus
- the antihyperglycemic drug is a biguanide such as metformin or buformin or a pharmaceutically acceptable salt thereof such as metformin hydrochloride .
- the binding agent may be any conventionally known pharmaceutically acceptable binder such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, ethylcellulose, poly ⁇ nethacrylate , waxes and the like. Mixtures of the aforementioned binding agents may also be used.
- the preferred binding agents are water soluble such as polyvinyl pyrrolidone having a weight average molecular weight of 25,000 to 3,000,000.
- the binding agent comprises approximately about 0 to about 40% of the total weight of the core and preferably about 3% to about 15% of the total weight of the core. «-
- the core may optionally comprise an absorption enhancer.
- the absorption enhancer can be any type of absorption enhancer commonly known in the art such as a fatty acid, a surfactant, a chelating agent, a bile salt or mixtures thereof .
- absorption enhancers examples include fatty acids such as capric acid, oleic acid and their monoglycerides, surfactants such as sodium lauryl sulfate, sodium taurocholate and polysorbate 80, chelating agents such as citric acid, phytic acid, ethylenediamine tetraacetic acid (EDTA) and ethylene glycol-bis ( ⁇ - aminoethyl ether) -N, N, N,N-tetraacetic acid (EGTA) .
- the core comprises approximately 0 to about 20% of the absorption enhancer based on the total weight of the core and most preferably about 2% to about 10% of the total weight of the core .
- the core of the present invention which comprises the antihyperglycemic drug, the binder which preferably is a pharmaceutically acceptable water soluble polymer and the absorption enhancer is preferably formed by wet granulating the core ingredients and compressing the granules with the addition of a lubricant into a tablet on a rotary press.
- the core may also be formed by dry granulating the core ingredients and compressing the granules with the addition of a lubricant into tablets or by direct compression.
- Other commonly known excipients may also be included into the core such as lubricants, pigments or dyes.
- the homogeneous core is coated with a semipermeable membrane, preferably a modified polymeric membrane to form the controlled release tablet of the invention.
- the semipermeable membrane is permeable to the passage of an external fluid such as water and biological fluids and is impermeable to the passage of the antihyperglycemic drug in the core.
- Materials that are useful in forming the semipermeable membrane are cellulose esters, cellulose diesters, cellulose triesters, cellulose ethers, cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, cellulose acetate propionate, and cellulose acetate butyrate .
- the most preferred semipermeable membrane material is cellulose acetate comprising an acetyl content of 39.3 to 40.3%, commercially available from Eastman Fine Chemicals.
- the semipermeable membrane can be formed from the above-described polymers and a flux enhancing agent.
- the flux enhancing agent increases the volume of fluid imbibed into the core to enable the dosage form to dispense substantially all of the antihyperglycemic drug through the passageway and/or the porous membrane.
- the flux enhancing agent can be a water soluble material or an enteric material.
- Some examples of the preferred materials that are useful as flux enhancers are sodium chloride, potassium chloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropyl methycellulose phthalate, cellulose acetate phthalate, polyvinyl alcohols, methacrylic acid copolymers and mixtures thereof.
- the preferred flux enhancer is PEG 400.
- the flux enhancer may also be a drug that is water soluble such as metformin or its pharmaceutically acceptable salts or a drug that is soluble under intestinal conditions. If the flux enhancer is a drug, the present dosage form has the added advantage of providing an immediate release of the drug which is selected as the flux enhancer .
- the flux enhancing agent comprises approximately 0 to about 40% of the total weight of the coating, most preferably about 2% to about 20% of the total weight of the coating.
- the flux enhancing agent dissolves or leaches from the semipermeable membrane to form paths in the semipermeable membrane for the fluid to enter the core and dissolve the active ingredient.
- the semipermeable membrane may also be formed with commonly known excipients such a plasticizer.
- plasticizers include adipate, azelate, enzoate, citrate, stearate, isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyl tri-n-butyl citrate, citric acid esters, and those described in the Encyclopedia of Polymer Science and Technology, Vol. 10 (1969), published by John Wiley & Sons.
- the preferred plasticizers are triacetin, acetylated monoglyceride, grape seed oil, olive oil, sesame oil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol, diethyloxalate, diethylmalate , diethylfumarate , dibutylsuccinate , diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate, tributylcitrate, glyceroltributyrate, and the like.
- amounts of from 0 to about 25%, and preferably about 2% to about 15% of the plasticizer can be used based upon the total weight of the coating.
- passageway includes an aperture, orifice, bore, hole, weaken area or an erodible element such as a gelatin plug that erodes to form an osmotic passageway for the release of the antihyperglycemic drug from the dosage form.
- erodible element such as a gelatin plug that erodes to form an osmotic passageway for the release of the antihyperglycemic drug from the dosage form.
- the membrane coating around the core will comprise from about 1% to about 5% and preferably about 2% to about 3% based on the total weight of the core and coating.
- the dosage form of the present invention may also comprise an effective amount of the antihyperglycemic drug that is available for immediate release.
- the effective amount of antihyperglycemic drug for immediate release may be coated onto the semipermeable --
- membrane of the dosage form or it may be incorporated into the semipermeable membrane.
- the dosage form will have the following composition: Preferred Most Preferred
- CORE drug 50-98% 75-95% binder 0-40% 3-15% absorption enhancer 0-20% 2-10% COATING : semipermeable polymer 50-99% 75-95% flux enhancer 0-40% 2-20% plasticizer 0-25% 2-15%
- the dosage forms prepared according to the present invention should exhibit the following dissolution profile when tested in a USP type 2 apparatus at 75 rpms in 900 ml of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37°C:
- various conventional well known solvents may be used to prepare the granules and apply the external coating to the tablets of the invention.
- various diluents, excipients, lubricants, dyes, pigments, dispersants etc. which are disclosed in Remington's Pharmaceutical Sciences, 1995 Edition may be used to optimize the formulations of the invention.
- a controlled release tablet containing 850 mg of metformin HCl and having the following formula is prepared as follows:
- the metformin HCl is delumped by passing it through a 40 mesh screen and collecting it in a clean, polyethylene- lined container.
- the povidone, K-30, and sodium tribasic phosphate are dissolved in purified water.
- the delumped metformin HCl is then added to a top-spray fluidized bed granulator and granulated by spraying the binding solution of povidone and sodium tribasic phosphate under the following conditions: inlet air temperature of 50-70°C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min.
- the granules are dried in the granulator until the loss on drying is less than 2%.
- the dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.
- the magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes. After blending, the granules are compressed on a rotary press fitted with 15/32" round standard concave punches (plain lower punch, upper punch with an approximately 1 mm indentation pin) .
- the core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear, in purified water.
- the Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C; atomization pressure of 28-40 psi; and spay rate of 10-15 ml/min.
- the core tablet is coated with the sealing solution until a theoretical coating level of approximately 2% is obtained.
- Figure 4 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example.
- FIG. 4 Also shown in Figure 4 is the in vivo metformin plasma profile of GLUCOPHAGE ® , a commercially available pharmaceutical product containing the drug metformin HCl.
- a controlled release tablet containing 850 mg of metformin HCl and having the following formula is prepared as follows:
- metformin HCl and sodium lauryl sulfate are delumped by passing them through a 40 mesh screen and collecting them in a clean, polyethylene -lined container.
- the povidone, K-90F is dissolved in purified water.
- the delumped metformin HCl and sodium lauryl sulfate are then added to a top-spray fluidized bed granulator and granulated by spraying with the binding solution of povidone under the following conditions : inlet air temperature of 50-70°C; atomization air pressure of 1-3 bars; and spray rate of 10-100 ml/min.
- the granules are dried in the granulator until the loss on drying is less than 2%.
- the dried granules are passed through a Comil equipped with the equivalent of an 18 mesh screen.
- the magnesium stearate is passed through a 40 mesh stainless steel screen and blended with the metformin HCl granules for approximately five (5) minutes. After blending, the coated granules are compressed on a rotary press fitted with 15/32" round standard concave punches (plain lower punch, upper punch with an approximately 1 mm indentation pin) .
- the core tablet is seal coated with an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear in purified water. The Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C; atomization pressure of 28-40 psi; and spay rate of 10-15 ml/min. The core tablet is coated with the sealing solution until a theoretical coating level of approximately 2% is obtained.
- an Opadry material or other suitable water-soluble material by first dissolving the Opadry material, preferably Opadry Clear in purified water. The Opadry solution is then sprayed onto the core tablet using a pan coater under the following conditions: exhaust air temperature of 38-42°C; atomization pressure of 28-40 psi; and spay rate of 10-15 ml/min.
- the core tablet is coated with the sealing solution until a theoretical coating level of approximately 2% is obtained.
- the cellulose acetate is dissolved in acetone while stirring with a homogenizer.
- the polyethylene glycol 400 and triacetin are added to the cellulose acetate solution and stirred until a clear solution is obtained.
- the clear coating solution is then sprayed onto the seal coated tablets in a fluidized bed coater employing the following conditions: product temperature of 16-22°C; atomization pressure of approximately 3 bars; and spray rate of 120-
- the sealed core tablet is coated until a theoretical coating level of approximately 3% is obtained.
- the resulting tablet is tested in simulated intestinal fluid (pH 7.5) and simulated gastric fluid (SGF) according to the procedure described in United States Pharmacopeia
- Figure 5 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example under fasting conditions.
- Figure 5 also shows the in vivo metformin plasma profile of the GLUCOPHAGE ® product under fasting conditions.
- Figure 6 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example
- Figure 6 also shows the in vivo metformin plasma profile of the GLUCOPHAGE ® product under fed conditions.
- Figures 5 and 6 clearly show that the dosage forms prepared in accordance with the present invention exhibit consistent bioavailability under both fed and fasting conditions while the GLUOPHAGE ® product's bioavailability decreases in the presence of food.
- a controlled release tablet containing 850 mg of metformin HCl and having the same formula as in Example 2 is prepared as described in Example 2 except that an additional hole was drilled on the plain side of the coated tablet.
- the additional hole had a diameter of approximately 1 mm.
- the resulting tablet is tested in simulated intestinal fluid (pH 7.5) and simulated gastric fluid (SGF) according to the procedure described in United States Pharmacopeia XXIII, Apparatus 2 @ 75 rpm and found to have the following release profile:
- Figure 7 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example when administered shortly after breakfast.
- Figure 7 also shows the in vivo metformin plasma profile of the
- GLUCOPHAGE ® product administered shortly after breakfast.
- Figure 8 depicts the in vivo metformin plasma profile of the sustained release product prepared in this Example when administered shortly after dinner. Figure 8 also
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Abstract
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000536365A JP4557424B2 (ja) | 1998-03-20 | 1999-03-19 | 単位コアを有する放出制御経口錠剤 |
EP99912705A EP1063971B1 (fr) | 1998-03-20 | 1999-03-19 | Comprimes oraux a noyau monolithique a liberation controlee |
DE69941115T DE69941115D1 (de) | 1998-03-20 | 1999-03-19 | Tablette mit einzelnem kern zur oralen verabreichung mit kontrollierter freisetzung |
KR1020007010441A KR20010071122A (ko) | 1998-03-20 | 1999-03-19 | 단일핵을 가진 방출제어형 정제 |
AU31019/99A AU739226B2 (en) | 1998-03-20 | 1999-03-19 | Controlled release oral tablet having a unitary core |
CA002324493A CA2324493C (fr) | 1998-03-20 | 1999-03-19 | Comprimes oraux a noyau monolithique a liberation controlee |
HK01108559A HK1037963A1 (en) | 1998-03-20 | 2001-12-06 | Controlled release oral tablet having a unitary core. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US09/045,330 US6099859A (en) | 1998-03-20 | 1998-03-20 | Controlled release oral tablet having a unitary core |
US09/045,330 | 1998-03-20 |
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WO1999047125A1 true WO1999047125A1 (fr) | 1999-09-23 |
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PCT/US1999/006024 WO1999047125A1 (fr) | 1998-03-20 | 1999-03-19 | Comprimes oraux a noyau monolithique a liberation controlee |
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US (5) | US6099859A (fr) |
EP (2) | EP2087889B1 (fr) |
JP (3) | JP4557424B2 (fr) |
KR (1) | KR20010071122A (fr) |
CN (1) | CN1158999C (fr) |
AU (1) | AU739226B2 (fr) |
CA (1) | CA2324493C (fr) |
DE (1) | DE69941115D1 (fr) |
ES (2) | ES2540972T3 (fr) |
HK (1) | HK1037963A1 (fr) |
WO (1) | WO1999047125A1 (fr) |
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WO2014184742A1 (fr) | 2013-05-13 | 2014-11-20 | Ranbaxy Laboratories Limited | Pharmaceutical compositions containing a biguanide and a low dose antidiabetic agent |
WO2015012633A1 (fr) | 2013-07-25 | 2015-01-29 | 씨제이헬스케어 주식회사 | Formulation complexe contenant de la metformine à libération prolongée et un inhibiteur de la hmg-coa réductase à libération immédiate |
US12097189B1 (en) | 2024-02-09 | 2024-09-24 | Astellas Pharma Inc. | Pharmaceutical composition for modified release |
Also Published As
Publication number | Publication date |
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JP4557424B2 (ja) | 2010-10-06 |
JP5427677B2 (ja) | 2014-02-26 |
US6495162B2 (en) | 2002-12-17 |
EP2087889A2 (fr) | 2009-08-12 |
AU3101999A (en) | 1999-10-11 |
CA2324493A1 (fr) | 1999-09-23 |
ES2540972T3 (es) | 2015-07-15 |
US20070154548A1 (en) | 2007-07-05 |
CA2324493C (fr) | 2006-02-14 |
JP2002506810A (ja) | 2002-03-05 |
US6099859A (en) | 2000-08-08 |
EP2087889A3 (fr) | 2009-09-02 |
US7919116B2 (en) | 2011-04-05 |
EP1063971A1 (fr) | 2001-01-03 |
HK1037963A1 (en) | 2002-03-01 |
CN1158999C (zh) | 2004-07-28 |
JP2010159290A (ja) | 2010-07-22 |
US20010024659A1 (en) | 2001-09-27 |
DE69941115D1 (de) | 2009-08-27 |
US8475841B2 (en) | 2013-07-02 |
AU739226B2 (en) | 2001-10-04 |
US20110195119A1 (en) | 2011-08-11 |
EP2087889B1 (fr) | 2015-06-17 |
ES2328308T3 (es) | 2009-11-11 |
CN1308520A (zh) | 2001-08-15 |
KR20010071122A (ko) | 2001-07-28 |
JP2013237689A (ja) | 2013-11-28 |
EP1063971A4 (fr) | 2006-05-24 |
EP1063971B1 (fr) | 2009-07-15 |
US20020064556A1 (en) | 2002-05-30 |
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